Immunohistochemical determination of mismatch repair gene product in colorectal carcinomas in a young indigenous African cohort.

BACKGROUND: Colorectal cancer (CRC) in the indigenous African population of South Africa is uncommon (age standardised incidence rates of 11.29 for males and 7.27/100 000 for females) and tends to occur at a young age. Lynch syndrome (LS), an inherited mismatch repair (MMR) gene abnormality, accounts for 3-4% of newly diagnosed CRCs in high incidence areas. There is some evidence that the contribution of an MMR abnormality to the overall CRC burden may be increased in low incidence areas. We aimed to determine the prevalence of MMR deficiency in an indigenous African population. METHODS: A cohort of 66 self-declared indigenous African patients, less than 50 years of age at diagnosis with CRC was identified from clinical and pathological records. The original histopathology was reviewed to confirm the diagnosis and features suggestive of MMR abnormality determined (pushing edge, mucinous, lymphocytic infiltration, Crohn's like reaction). Where sufficient tissue was available, samples were sectioned and stained for the four MMR proteins. RESULTS: Histopathological examination confirmed adenocarcinoma in 31 individuals. At least one feature suggestive of MMR was identified in 22 of these specimens. Twenty-seven cases were stained for all four MMR proteins using standard immunohistochemistry (IHC). MMR deficiency was found in 37% (n = 10/27) of cases. Median age of diagnosis was 35 years in the MMR-proficient group and 44 years in the MMR-deficient group, p < 0.008. No other significant differences between the groups were noted. CONCLUSION: MMR deficiency was common in colorectal carcinomas in the older patients in this cohort, but very young indigenous Africans CRCs do not appear to result from mismatch repair gene mutations.

Changes in surgical practice in 85 South African hospitals during COVID-19 hard lockdown.

BACKGROUND: In preparation for the COVID-19 pandemic, South Africa (SA) began a national lockdown on 27 March 2020, and many hospitals implemented measures to prepare for a potential COVID-19 surge. OBJECTIVES: To report changes in SA hospital surgical practices in response to COVID-19 preparedness. METHODS: In this cross-sectional study, surgeons working in SA hospitals were recruited through surgical professional associations via an online survey. The main outcome measures were changes in hospital practice around surgical decision-making, operating theatres, surgical services and surgical trainees, and the potential long-term effect of these changes. RESULTS: A total of 133 surgeons from 85 hospitals representing public and private hospitals nationwide responded. In 59 hospitals (69.4%), surgeons were involved in the decision to de-escalate surgical care. Access was cancelled or reduced for non-cancer elective (n=84; 99.0%), cancer (n=24; 28.1%) and emergency operations (n=46; 54.1%), and 26 hospitals (30.6%) repurposed at least one operating room as a ventilated critical care bed. Routine postoperative visits were cancelled in 33 hospitals (36.5%) and conducted by telephone or video in 15 (16.6%), 74 hospitals (87.1%) cancelled or reduced new outpatient visits, 64 (75.3%) reallocated some surgical inpatient beds to COVID-19 cases, and 29 (34.1%) deployed some surgical staff (including trainees) to other hospital services such as COVID-19 testing, medical/COVID-19 wards, the emergency department and the intensive care unit. CONCLUSIONS: Hospital surgical de-escalation in response to COVID-19 has greatly reduced access to surgical care in SA, which could result in a backlog of surgical needs and an excess of morbidity and mortality.

Multivisceral resection of locally advanced colorectal cancer in an African referral centre.

BACKGROUND: Colorectal cancer (CRC) is common and often presents with advanced disease in Africa. Multivisceral resection (MVR) improves survival in locally advanced (T4b) CRC. The aim was to describe the management and outcomes of patients with clinical T4b CRC without metastatic disease who underwent MVR. METHODS: A retrospective review of patients with T4 CRC who underwent MVR between January 2008 and December 2013. RESULTS: Four hundred and ninety-four patients were included. Of the 158 with suspected T4 cancer, 44 had MVR, of which one was excluded due to metastases. The mean age was 64 years. The male to female ratio was 1:1. The most commonly resected extra-colorectal structure was the abdominal wall (21%). The median survival was 68 months (SD 13.9). The 5-year disease free (DFS) and overall survival (OS) were 46% and 55%, respectively. Survival of patients with colon and rectum cancer was similar. Intraoperative tumour spillage, vascular/perineural invasion, and anastomotic leakage were independent predictors of survival. CONCLUSION: Multivisceral resection of locally advanced (T4b) CRC is feasible in the African context. Complete resection improves survival and should be the goal.

Bowel preparation for colonoscopy: is diet restriction necessary?

BACKGROUND: Bowel preparation is essential for quality colonoscopy. Although most bowel preparation regimens recommend dietary restriction for 24 to 48 hours before the procedure, the evidence for this is poor. This study aimed to investigate whether dietary restriction during bowel preparation improves the quality of colonoscopy. METHODS: A prospective, randomised controlled pilot study in which the dietary restriction (DR) group (control) was instructed not to ingest high fibre foods for 48 hours prior to the use of a polyethylene glycol (PEG) bowel preparation. The non-dietary restriction (NDR) group were given no dietary instruction but received instructions for the use of the PEGbased preparation. On the day of colonoscopy, the quality of the bowel effluent was assessed, and additional preparation given as necessary. The primary endpoint was quality of bowel cleansing using the Harefield Cleansing Scale during colonoscopy. The secondary endpoints were the need for additional bowel preparation and the quantity of additional bowel preparation given prior to endoscopy. Data were analysed on an intention to treat basis. RESULTS: Twenty-three participants were randomised to the intervention group and thirty-four to the control group. Patient demographics were similar in both groups. Dietary restriction did not influence the success rate of bowel preparation: 97% successful bowel preparation in the DR group, vs 91% successful bowel preparation in the NDR group (p = 0.559). Additional bowel preparation requirement were similar in both groups: 35% in the DR group vs 39% in the NDR group (p = 0.768). Mean amount of additional bowel preparation required was similar: 560 ml in the DR group vs 460 ml in the NDR group (p = 0.633). CONCLUSION: The quality of bowel preparation was comparable in patients with and without dietary restrictions prior to colonoscopy. Non-restrictive diets prior to bowel preparation should be considered to increase compliance. The sample size of this pilot study prohibited definite statistical conclusions but demonstrated this to be a reasonable methodology for a larger study.

Requiem for Nigro or is anal squamous carcinoma still a surgical problem: Abdominoperineal excision rather than a defunctioning stoma?

BACKGROUND: Combined multimodal treatment (CMT) is the preferred treatment for anal squamous carcinoma with radical surgery reserved for treatment failure. Some patients require a defunctioning stoma prior to CMT. Successful closure of such a stoma is unlikely. Abdominoperineal excision (APE) may be suitable as primary treatment in these patients. METHOD: A retrospective review of all patients with anal squamous carcinoma was undertaken. Patients who required defunctioning colostomies prior to CMT were analysed for potential resectability of tumour prior to CMT and rate of permanent stoma. OBJECTIVE: To evaluate organ preservation in the treatment of anal squamous cancer and the closure rate of pre-treatment, temporary diverting colostomy, thereby assessing whether APE could be offered as primary treatment in those requiring a pre-treatment colostomy. RESULTS: One hundred and twenty-five patients were included of which 58 were males. The mean age was 56 years. 107 were treated with curative intent. Six received primary APE and 12 salvage APE. Thirty (22 males) required pretreatment diverting colostomies. Three (10%) stomas were successfully reversed. Forty-eight (38%) of the 125 completed treatment with a permanent colostomy. Six patients who needed a stoma prior to CMT were deemed resectable. CONCLUSION: Organ preservation was not possible in about a third of patients. Defunctioning stomas prior to CMT were likely to be permanent. We propose that APE could be considered as an alternative in selective cases where the tumour is resectable with low morbidity and a stoma is indicated.

Measurement of pleural pressure swings with a fluid-filled esophageal catheter vs pulmonary artery occlusion pressure.

PURPOSE: Pleural pressure measured with esophageal balloon catheters (Peso) can guide ventilator management and help with the interpretation of hemodynamic measurements, but these catheters are not readily available or easy to use. We tested the utility of an inexpensive, fluid-filled esophageal catheter (Peso) by comparing respiratory-induced changes in pulmonary artery occlusion (Ppao), central venous (CVP), and Peso pressures. METHODS: We studied 30 patients undergoing elective cardiac surgery who had pulmonary artery and esophageal catheters in place. Proper placement was confirmed by chest compression with airway occlusion. Measurements were made during pressure-regulated volume control (VC) and pressure support (PS) ventilation. RESULTS: The fluid-filled esophageal catheter provided a high-quality signal. During VC and PS, change in Ppao (∆Ppao) was greater than ∆Peso (bias = -2 mm Hg) indicating an inspiratory increase in cardiac filling. During VC, ∆CVP bias was 0 indicating no change in right heart filling, but during PS, CVP fell less than Peso indicating an inspiratory increase in filling. Peso measurements detected activation of expiratory muscles, development of non-west zone 3 lung conditions during inspiration, and ventilator-triggered inspiratory efforts. CONCLUSIONS: A fluid-filled esophageal catheter provides a high-quality, easily accessible, and inexpensive measure of change in pleural pressure and provided insights into patient-ventilator interactions.

Comparative study of extralevator vs. conventional abdominoperineal excision in a single centre in the developing world.

ABSTRACT: Abdominoperineal excision (APE) is used to resect cancers in the distal rectum and anus where sphincterpreserving surgery is not possible. It is associated with increased local recurrence rates compared to anterior resection. The extralevator abdominoperineal excision (ELAPE) was developed to reduce local recurrence and was widely adopted without sound evidence. AIM: To compare the short-term (2 years) outcomes of patients managed with ELAPE to those with conventional APE in a single institution in a developing country. METHOD: A prospective database on all patients treated with prone ELAPE from 2010 to 2014 was compared to patients treated with conventional APE. Patient demographics, tumour characteristics, intra-operative tumour perforation, involvement of the circumferential resection margin (CRM), surgical complications and mortality are reported. RESULTS: Fifty-six patients were treated with APE of which 29 were male. Median age was 56. Thirty underwent conventional APE (16 male; 14 female) and 26 underwent ELAPE (15 male; 11 female). The groups were similar in age, tumour histology, height above anal verge clinical staging and response to neoadjuvant treatment. Perineal closure techniques in both cohorts were similar. There was no difference in intra-operative tumour perforation, involvement of the CRM, perineal wound complications or 30-day mortality in the 2 groups. CONCLUSION: There is no difference in the important short-term outcomes of conventional APE when compared to ELAPE.

Refeeding enteroclysis as an alternative to parenteral nutrition for enteric fistula.

AIM: Refeeding enteroclysis is one method of giving artificial nutritional support to patients with enterocutaneous fistula. This study compares the results of this technique with parenteral nutrition or nutrition given via a proximal stoma. METHOD: All patients admitted to our intestinal failure unit with a proximal enteric fistula and managed with refeeding enteroclysis over a 4-year period were included and compared with a matched group of patients managed without using this technique. RESULTS: Twenty patients (15 men) with a proximal enteric fistula received chyme refeeding down the distal limb of the fistula. This was established at a mean of 14 days after admission to the unit and total parenteral nutrition could be weaned off by 20 days. The mean output from the proximal limb was 1800 ml and the mean volume refed down the distal limb was 1220 ml per day. Additional enteric feed was given to 12 patients. No patient was given pharmacological agents to delay gastrointestinal transit or additional intravenous water and electrolyte for most of the time after refeeding was established. There were no complications or deaths related to chyme refeeding. CONCLUSION: Refeeding enteroclysis is feasible in selected patients with a proximal enteric fistula or stoma. Adequate nutrition, water and electrolyte balance can be achieved without resorting to parenteral infusions.

No evidence of genetic anticipation in a large family with Lynch syndrome.

Lynch syndrome is the commonest inherited cause of colorectal cancer (CRC). Genetic anticipation occurs when the age of onset of a disorder decreases in successive generations. It is controversial whether this occurs in Lynch syndrome. Previous studies have included heterogenous groups of subjects from multiple families, including subjects with a clinical diagnosis (based on family history) as well as those with proven germline mismatch repair gene mutations. The purpose of this study was to determine whether genetic anticipation occurs in mismatch repair gene carriers from a single Lynch syndrome family. This study includes members of a single family known to carry an MLH1 gene mutation who are proven germline mutation carriers or obligate carriers (based on their offspring's mutation status). Evidence of genetic anticipation (determined by age of onset of first CRC) was sought in two ways: Firstly, subjects were grouped as parent-child pairs and individuals were compared with their own offspring; secondly they were grouped by generation within the family tree. The Kaplan-Meier technique was used to adjust for variable follow up times. The family tree consisted of 714 subjects. Ninety-two subjects over five generations were included in the study. There was no evidence of genetic anticipation over the generations. (P = 0.37). Similarly, in the 75 parent-child pairs identified, age of onset of CRC was similar for parents and children (P = 0.51). We could not identify any evidence of genetic anticipation in mutation carriers from a single family with Lynch syndrome.

Mismatch repair deficiency in colorectal cancer patients in a low-incidence area.

BACKGROUND: In a previous study we identified 206 patients with colorectal adenocarcinoma in the Northern Cape province of South Africa, diagnosed between January 2002 and February 2009. The age-standardised incidence was 4.2/100 000 per year world standard population. This is 10% of the rate reported in First-World countries. In high-incidence areas, the rate of abnormal mismatch repair gene expression in colorectal cancers is 2 - 7%. OBJECTIVES: The aim of this study was to determine the prevalence of hMLH1- and hMSH2-deficient colorectal cancer in the Northern Cape. METHODS: Formalin-fixed paraffin wax-embedded tissue blocks from 87 colorectal adenocarcinomas identified in the previous study were retrieved. Standard immunohistochemical staining methods were used to detect the expression of hMLH1 and hMSH2 (i.e. products of the hMLH1 and hMSH2 genes) in the tumours using heat-induced antigen retrieval and diaminobenzidene as a chromogen. Results. In 8 blocks there was insufficient tumour tissue and in 1 case the immunohistochemical staining failed, probably owing to poor fixation, leaving 78 cases for analysis. In 11 cases hMLH1 was deficient and in 6 cases hMSH2 was deficient. Overall, 21.8% of cancers were deficient for hMLH1 or hMSH2. CONCLUSION: Presuming that 80% of all hMLH1 deficiencies are due to hypermethylation of the gene, we found 10.5% of colorectal cancers in an area with a low incidence of colorectal cancer to be deficient in the product of the mismatch repair gene/s. This is approximately three times the reported rate in high-incidence areas.

Stenting as first-line management for all patients with nonperforating left-sided obstructing colorectal cancer.

AIM: Since 2005, we have used self-expanding metal stents (SEMS) as primary treatment for all patients with left-sided obstructing colorectal cancer without evidence of perforation. The purpose of this study was to assess the safety and efficacy of this treatment. METHOD: This was a prospective study of consecutive patients with left-sided obstructing colorectal cancer without perforation or peritonitis treated between January 2005 and June 2009. SEMS placement was attempted in all cases. Emergency surgery was reserved for patients in whom a stent placement failed. After successful decompression, surgery was offered to patients with potentially curable disease. RESULTS: Seventy-seven patients were included, with successful SEMS placement in 60/77 (78%) patients, 25 as a bridge to surgery and 35 for palliation. Immediate complications occurred in two (3%) cases. There was no mortality. Of 35 patients in whom SEMS was for palliation, 32 (91%) avoided surgery altogether. A stoma was fashioned in 5 (8.3%) of the 60 patients who were successfully stented, and in 12 (71%) of the 17 patients in whom stenting failed (P = 0.0001). CONCLUSION: A SEMS-based management protocol for patients with large bowel obstruction due to colorectal cancer is safe and effective.

Treatment of carcinoma of the anal canal at Groote Schuur Hospital.

OBJECTIVES: Chemoradiation is the treatment of choice for squamous carcinoma of the anal canal, resulting in the same local control rates as surgery but with the advantage of organ function preservation. We aimed to review all cases of anal canal carcinoma treated at Groote Schuur Hospital between 2000 and 2004 and to assess treatement outcome. METHODS: The records for 31 patients presenting during this period were reviewed. Patient and tumour characteristics were recorded. Twenty-six patients were treated with chemoradiation. Local failure-free, colostomy-free and overall survival were calculated using the Kaplan-Meier method. RESULTS: Compared with the literature, the median patient age was younger and the stage was more advanced in this study. The complete response rate for all stages with chemoradiation was 80%. The local failure-free survival at 5 years was 60.7%. Colostomy-free and overall survival at 5 years were 59.2% and 65.6%, respectively. CONCLUSIONS: The patients presented with locally advanced disease. Chemoradiation is effective treatment for this group of patients and the majority avoid a permanent colostomy as they preserve anal sphincter function.

Colonic stenting as a bridge to surgery in malignant large-bowel obstruction: a report from two large multinational registries.

OBJECTIVES: To date, this is the largest prospective series in patients with malignant colorectal obstruction to evaluate the effectiveness and safety of colonic self-expanding metal stents (SEMSs) as an alternative to emergency surgery. SEMSs allow restoration of bowel transit and careful tumor staging in preparation for elective surgery, hence avoiding the high morbidity and mortality associated with emergency surgery and stoma creation. METHODS: This report is on the SEMS bridge-to-surgery subset enrolled in two multicenter international registries. Patients were treated per standard of practice, with documentation of clinical and procedural success, safety, and surgical outcomes. RESULTS: A total of 182 patients were enrolled with obstructive tumor in the left colon (85%), rectum (11%), or splenic flexure (4%). Of these patients, 86% had localized colorectal cancer without metastasis. Procedural success was 98% (177/181). Clinical success was 94% (141/150). Elective surgery was performed in 150 patients (9 stomas) and emergency surgery in 7 patients for treatment of a complication (3 stomas). The overall complication rate was 7.8% (13/167), including perforation in 3% (5/167), stent migration in 1.2% (2/167), bleeding in 0.6% (1/167), persistent colonic obstruction in 1.8% (3/167), and stent occlusion due to fecal impaction in 1.2% (2/167). One patient died from complications related to surgical management of a perforation. CONCLUSIONS: SEMSs provide an effective bridge to surgery treatment with an acceptable complication rate in patients with acute malignant colonic obstruction, restoring luminal patency and allowing elective surgery with primary anastomosis in most patients.

Surgery for colonic cancer in HNPCC: total vs segmental colectomy.

AIM: The high reported risk of metachronous colon cancer (MCC) in hereditary nonpolyposis colorectal cancer (HNPCC) has led some authors to recommend total colectomy (TC) as the preferred operation for primary colon cancer, but this remains controversial. No previous study has compared survival after TC with segmental colectomy (SC) in HNPCC. The aim of this study was to determine the risk of developing MCC in patients with genetically proven HNPCC after SC or TC for cancer, and to compare their long-term survival. METHOD: This is a prospective cohort study of all patients referred to our unit between 1995 and 2009 with a proven germline mismatch repair gene defect, who had undergone a resection for adenocarcinoma of the colon with curative intent. All patients were offered annual endoscopic surveillance. RESULTS: Of 60 patients in the study, 39 had TC as their initial surgery and 21 had SC. After 6 years follow up, MCC occurred in eight (21%) SC patients and in none of the TC patients (P = 0.048). The risk of developing MCC after SC was 20% at 5 years. Colorectal cancer-specific survival was better in TC patients (P = 0.048) but overall survival of the two groups was similar (P = 0.29). CONCLUSION: Patients with HNPCC have a significant risk of MCC after SC. This is eliminated by performing TC as the primary operation for colonic cancer.

Lynch syndrome: the influence of environmental factors on extracolonic cancer risk in hMLH1 c.C1528T mutation carriers and their mutation-negative sisters.

Lynch Syndrome (LS) is a cancer susceptibility syndrome caused mostly by mutations in the mismatch repair genes, hMLH1, hMSH2 and hMSH6. Mutation carriers are at risk of colorectal and endometrial cancer and, less frequently, cancer of the ovaries, stomach, small bowel, hepatobiliary tract, ureter, renal pelvis and brain. The influence of environmental factors on extracolonic cancer risk in LS patients has not been investigated thus far. The aim of this study was to investigate some of these factors in South African females carrying the hMLH1 c.C1528T mutation and their mutation-negative relatives. Data were collected from 87 mutation-positive females and 121 mutation-negative female relatives regarding age, cancer history, hormonal contraceptive use, parity, duration of breast feeding, height, weight and age at first birth, last birth, menarche and menopause. Influence of these factors on cancer risk was analysed by mixed-effects generalised linear models. Extracolonic cancer occurred in 14% (12/87) of mutation-positive females versus 7% (8/121) of mutation-negative females, (P = 0.0279, adjusted for age and relatedness between women). Breast cancer was the most common extracolonic cancer. An association was found for oral contraceptive use and extracolonic cancer risk in mutation-negative females only. No association was found for any of the other risk factors investigated, when adjusted for age. This might be due to the scarcity of extracolonic cancers in our data. Future knowledge on the influence of additional environmental factors on cancer risk in LS females can lead to evidence-based lifestyle advice for mutation carriers, thereby complementing the prevention strategies available today. In addition, it can contribute to an integrated model of cancer aetiology. Therefore, this study should be taken as a thrust for further research.